ZA200309860B

ZA200309860B - Substituted anilinic piperidines as MCH selective antagonists.

Info

Publication number: ZA200309860B
Application number: ZA200309860A
Authority: ZA
Inventors: Mohammad R Marzabadi; John Wetzel; John E Deleon; Yu Jiang; Chien-An Chen; Kai Lu; Bharat Lagu
Original assignee: Lundbeck & Co As H
Priority date: 2001-07-05
Filing date: 2002-07-03
Publication date: 2005-03-11

Description

. SUBSTITUTED ANILINIC PIPERIDINES AS MCH SELECTIVE

ANTAGONISTS

. 5

BACKGROUND OF THE INVENTION

This application is a continuation-in-part of U.S.

Serial No. 10/042,582, filed January 9, 2002, and of

U.S. Serial No. 09/899,794, filed July 5, 2001, the contents of both of which are hereby incorporated by reference into the subject application.

Throughout this application, various publications are referenced in parentheses by author and vyear. Full citations for these references may be found at the end of the specification immediately preceding the sequence listings and the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from salmonid (teleost fish) pituitaries (Kawauchi et al., 1983). In fish the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of o-MSH.

Mammalian MCH (19 amino acids) is highly conserved ' between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state,

memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994;

Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent

Nature publication (Ou et al., 1996) demonstrating that

MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats . when injected into the lateral ventricles (Rossi et al., 1997). MCH also has been reported to functionally : antagonize the behavioral effects of o-MSH (Miller et . al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991; Knigge et al., 1996) .

Although the biological effects of MCH are believed to be mediated by specific receptors, binding sites for MCH have not been well described. A tritiated ligand ([%H]-

MCH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor Bp.x were determined (Drozdz and

Eberle, - 1995). Radioiodination of the. tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, the radioiodination of the MCH analogue [Phe!?,Tyr!’]-MCH was successful (Drozdz et al., 1995); the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PCl2, and COS cells. In G4F-7 cells, the Kp = 0.118nM and the \ Bmax ~1100 sites/cell. Importantly, the binding was not inhibited by «a-MSH but was weakly inhibited by rat ANF (Ki = 116 nM vs. 12 nM for native MCH) (Drozdz et al., 1995). More recently specific MCH binding was reported in transformed keratinocytes (Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photo- crosslinking studies suggest that the receptor is a membrane protein with an apparent molecular weight of 45-50 kbDaltons, compatible with the molecular weight range of the GPCR superfamily of receptors. No radioautoradiographic studies of MCH = receptor is localization using this ligand have been reported as yet.

The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. The role of MCH in feeding is the best characterized of its potential clinical uses. MCH is expressed in the lateral hypothalamus, a brain area implicated in the regulation of thirst and hunger : (Grillon et al., 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al., 1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Hervé and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive ‘ perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH to stimulate feeding in rats (Rossi et ' al., 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al., 1996), and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased (Sahu, 1998). MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al., 1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.

In all species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant ’ location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called “extrapyramidal” motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic : areas, and reciprocal <connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with ’ appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as

Parkinson’s disease and Huntingdon’s Chorea in which extrapyramidal circuits are known to be involved. ] Human genetic linkage studies have located authentic 5 hMCH loci on chromosome 12 (12g23-24) and the variant hMCH loci on chromosome 5 (5gl2-13) (Pedeutour et al., 1994). Locus 12g23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992). This disease comprises neurodegenerative . disorders, including an olivopontocerebellar atrophy.

Furthermore, the gene for Darier’s disease, has been mapped to locus 12g23-24 (Craddock et al., 1993).

Dariers’ disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical . patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for

SCA2 or Darier’s disease. Interestingly, diseases with high social impact have been mapped to this locus. : Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 512-13 using genetic linkage analysis (Melki ‘ et al., 1990; Westbrook et al., 1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5ql1.2-13.3 (Sherrington et al., 1988; Bassett et al., 1988; Gilliam a et al., 1989). The above studies suggest.that MCH may play a role in neurodegenerative diseases and disorders of emotion. v

Additional therapeutic applications for . MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female } rats. MCH transcripts and MCH peptide were found within germ cells in .testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996) . MCH ‘injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996).

In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-

MCH antiserum inhibited LH release (Gonzalez et al., 1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). MCH has been reported to influence release of pituitary hormones including

ACTH and oxytocin. MCH analogues may also be useful. in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that

MCH-containing neurons may participate in the neural circuitry underlying PTZ-induced seizure (Knigge and

Wagner, 1997). MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage. and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the ] periaqueductal grey (PAG) by MCH-positive fibers.

Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996) .

Together with anatomical data reporting the presence of

MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.

The identification of a G-protein coupled receptor for

MCH has recently been published (Chambers et al., 1999;

Saito et al., 1999). These groups identified MCH as the endogenous ligand for the human orphan G-protein coupled receptor SLC-1 (Lakaye et al., 1998). The rat homologue of this receptor (mow called MCH-1) was reported to be localized in regions of the rat brain associated with feeding behavior (e.g. dorsomedial and ventromedial hypothalamus) . The link between MCH-1 and the effects of MCH on feeding has been strengthened by recent reports on the phenotype of MCH-1 knockout mice. Two groups have shown independently (Marsh et al, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1 receptor gene (MCH-1 knockout) in mice results in animals that are hyperphagic but are lean and have decreased body mass relative to wild-type littermates.

The decrease in body mass is attributed to an increase in metabolism. Each group demonstrated that the MCH-1 knockout mice are resistant to diet-induced obesity, and generally exhibit weights similar to. littermates maintained on regular chow. :

Finally, synthetic antagonist molecules for the MCH-1 receptor have now been described in the literature.

Bednarek et al. (2002) have reported on the synthesis of high affinity peptide antagonists of MCH-1. In addition, a small molecule antagonist of MCH-1 has been described by Takekawa et al. (Takekawa et al., 2002). ] This compound, T-226296, exhibits high affinity for the

MCH-1 receptor (~ 5-9 nM for rat and human MCH-1), and was shown to inhibit food intake induced by the intracerebroventricular application of MCH. These data . validate the strategy of using an MCH-1 receptor antagonist to treat obesity. )

Furthermore, in our own studies, we have tested MCH1 antagonists in several animal models that are well known as predictive for the efficacy of compounds in humans (Borowsky, et al., in press; unpublished data). These experiments indicate that MCHl1 antagonists are useful to treat obesity, depression, anxiety, as well as urinary disorders.

As used in this invention, the term “antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.

Conversely, the term “agonist” refers to a compound which binds to, and increases activity of, a receptor as compared - with the activity of the receptor in the : absence of any agonist.

In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCH1) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vitro assays is disclosed. The in vitro receptor binding assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.

Furthermore, the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCH1 receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject. Furthermore, the compounds of the present invention may be used to treat urinary disorders. oq

Summary of the Invention

This invention provides a compound having the structure: : Sth ;

Rs N—H o=(

R2 wherein R; is hydrogen, straight chained or branched

C,-C; alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, =-CH;, -CFi, -COR;, -CO;R;, phenyl, phenoxy or straight chained or branched C;-C; alkyl; wherein R, is straight-chained or branched C;-C, alkyl or cyclopropyl; wherein Ry; is aryl or heteroaryl, wherein the aryl or : heteroaryl is optionally substituted with one or more -f, -C1, -Br, -I, -CN, -NO,, straight chained or branched C;-C; alkyl; wherein A is -H, -F, -Cl, -Br, -CN, -NO,, -CORj;, -COzRj3, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluorocalkyl; wherein X is O or NH; and . 25 wherein n is an integer from 0 to 5 inclusive.

In one embodiment, Ry, is aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NOz, -CORz, . -CO,R,, straight chained or branched C;-C; alkyl; . 5 wherein Ri is phenyl; wherein A is H; and wherein X is O.

In one embodiment, R; is isopropyl. : In one embodiment, the compound has the structure: 0

N

= . 15 In one embodiment, compound has the structure: / oO 0O— & OQ \ .

In one embodiment, R; is hydrogen, straight chained or ) branched C;-C; alkyl; and wherein R; is aryl.

In one embodiment, R, is isopropyl; and A is hydrogen.

In one embodiment, the compound has the structure: . N =

In one embodiment, the compound has the structure:

N

=

The present invention also provides a compound having the structure: : 10 . :

Ry N \ /

In : oO N—H o=<(

R2 wherein R; is aryl or heteroaryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO;, -0OCH;, phenoxy, fused cyclopentanyl, straight chained or branched C;-C; alkyl, monofluorocalkyl or polyfluorocalkyl; wherein R; is straight-chained or branched C;-C, alkyl or ’ cyclopropyl;

wherein A is -H, -F, -Cl, - Br, -CN, -NO,, straight chained or branched C;-C; alkyl, monofluoroalkyl or . polyfluoroalkyl; and . 5 wherein n is an integer from 1 to 5 inclusive.

In one embodiment, R; is aryl optionally substituted with one or more -F, -Cl, -Br, -I or straight chained or branched C;-C, alkyl; and wherein A is H.

In one embodiment, R; is isopropyl; and wherein n is 2.

In one embodiment, the compound has the structure:

OC

Pe ’ © 0

In one embodiment, the compound has the structure: 0 0

In one embodiment, the compound has the structure: 0) 0)

F N nA — :

In one embodiment, R; is thienyl; and wherein A is H.

In one embodiment, R; is isopropyl.

In one embodiment, the compound has the structure: 0

Sa Z s N nN

The invention provides a compound having the structure:

A

=|= ,—N

W \_¢

N—H no . o ={

Ry wherein W is . . H A

SA as or YZ ;

NR

Ry H wherein each R; is independently hydrogen, methyl or ) 20 ethyl;

wherein R; 18 straight- chained or branched GC;-Cq alkyl or cyclopropyl; wherein Ry is hydrogen, aryl or heteroaryl, wherein the } 5 aryl or heteroaryl is optionally substituted with one or more -H, -F, -Cl, -Br, -I, -CN, -NO,, straight chained or branched C;-C; alkyl. wherein each A is independently -H, -F, -Cl, -Br, -CN, -NO,, -COR;, -CO;R3, straight chained or branched C;-Cy alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is 0, NRi;, CO or may be absent; and wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, straight chained or branched C;-C; alkyl.

In one embodiment, W is

H A

VA

=

H ; and wherein X is O or may be absent.

In one embodiment, R, is isopropyl. :

In one embodiment, the compound has the structure:

NO) : 0 “A

O .

F F

In one embodiment, the compound has the structure:

OL

In one embodiment, W is

R4

In one embodiment, A is -H, -F, -Cl, -Br.

In one embodiment, R; is isopropyl; and A is hydrogen.

In one embodiment, the compound has the structure:

N 0}

J XL

This invention provides a compound having the structure: 5 . +

WwW =|=

N—

N—H o=< -

R2 wherein W is

B B

N ~ B Nx B 0 : ox

P N F N

\ 3 :

Ry Ry wherein R; is hydrogen, straight chained or branched

C,-Cy alkyl, aryl or heteroaryl, wherein the aryl or hetercaryl is optionally substituted with one or more -F, -C1l, ~-Br, -CN, -NO5, -QOCHj, -CO,CHa,, -CF,, phenyl, straight chained or branched C;-C; alkyl; wherein R, is straight-chained or branched C;-C, alkyl or cyclopropyl; wherein A is -H, -F, -Cl, -Br, -CN, -NO;, -COR;, -CO2R), . straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluorocalkyl or phenyl. wherein each B is independently -H, -F, -Cl, -Br, -I,

-CN, -NO,, -COR;, -CO;R;, - OCH;, -OCF,, -CF,;, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more -F, -Cl, -Br, -CN, -NO,, -COR;, -COzRi, -OCH,, -OCF,, -CF3 or straight chained or branched Cl -C3 : alkyl,

In one embodiment, W is

ZN

Ri.

In one embodiment, R; is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -NOp, straight chained or branched C.-C; alkyl. : In one embodiment, R; is isopropyl.

In one embodiment, the compound has the structure:

OQ

N cd A

CL cl N }

In one embodiment, the compound has the structure: . N ) 9

N . ord 0

N

This invention provides a compound having the structure:

A

=|= = [/3=N \ / \ J Ry N—H

N =<

R4 Ro wherein R; is hydrogen, straight chained or branched

C;-C, alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -CN, -NO;, -CF;, -OCH3, straight chained or branched C;-C3 alkyl; . wherein R, is straight-chained or branched C;-C, alkyl or cyclopropyl; wherein R; is -H, -F, -Cl, -Br, -I, -CN, -NOp, -CFs, -OCH;, or straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl, or a. phenyl ring fused to C¢ and C; of the indole moiety; wherein Rs, is hydrogen or aryl optionally substituted } with one or more -F, -Cl, -Br, -I, -CN, -NO,, -CFj, straight chained or branched C;-C; alkyl;

wherein A is -H, -F, -Cl1, -Br, -CN, -NOj, straight. } chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; and . 5 wherein n is an integer from 2 to 4 inclusive.

In one embodiment, R; is -H, -F, -Cl, -Br, -I, -CN, -NOz, -OCF5; or -OCH;; and wherein R, is hydrogen or phenyl optionally substituted with one or more -F, -Cl or -CF;.

In one embodiment, R;, is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -NO;, -CF;, -OCH; or straight chained or branched C;-C3 alkyl;

In one embodiment, R; is isopropyl.

In one embodiment, the compound has the structure:

OQ

N

3 0

N

N :

In one embodiment, the compound has the structure:

F x ) FO : N N Ny~

Oo

Cl

In one embodiment, the compound has the structure: &, \ as

This invention provides a compound having the structure:

A

=|=

Rs N :

Ri ~~ \ 7

N—X N-H 0 R2 wherein each R; is independently hydrogen ox CHj; wherein R, is straight-chained or branched C;-C, alkyl or cyclopropyl; wherein R; is benzyl or phenyl , wherein the benzyl or . phenyl is optionally substituted with a methylenenedioxy group or one or more -F or -Cl;

wherein A is -H, -F, -Cl, - Br, -CN, -NO,, straight chained or branched C;-C; alkyl, monofluoroalkyl or : polyfluoroalkyl; : 5 wherein X is (CH;)2, COCH; or CONH

In one embodiment, R; is phenyl optionally’ substituted with one or more -F; and wherein A is hydrogen.

In one embodiment, X is CONH.

In one embodiment, R, is methyl.

In one embodiment, the compound has the structure:

Fx ® F 0) (ON NTN NY o— N (0)

In one embodiment, the compound has the structure: c ve

N

Og pa av,

N-X N-H oO o={ 0 i wherein each Y is independently hydrogen or -F.

In one embodiment, the compound has the structure:

} F

Fx : F (0) (ON NNN NY o— N (6)

In one embodiment, the compound has the structure:

F

F o

Ny ANN o— N (0)

In one embodiment, R; is benzyl optionally substituted with a methylenedioxy group or one or more -F Or -Cl.

In one embodiment, the compound has the structure:

RF

=) aS 4

N

: R4 Ri ~~ OQ

N—X N-H 0 SP . i5 wherein each Y is independently hydrogen or -F.

In one embodiment, the compound has the structure: . F. . ] 0) nA ANN 0

N o— N oO

In one embodiment, the compound is enantiomerically pure. :

In one embodiment, the compound is diastereomerically pure.

In one embodiment, the compound is enantiomerically and diastereomerically pure.

This invention also provides a pharmaceutical composition comprising a therapeutically amount of a ] compound of the invention and a pharmaceutically acceptable carrier.

In one embodiment, the amount of the compound is from about 0.0lmg to about 500mg. :

In one embodiment, the amount of the compound is from about 0.lmg to about 60mg.

In one embodiment, the amount of the compound is from . 25 about 1lmg to about 20mg.

In one embodiment, the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.

In one embodiment, the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet.

In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.

The invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable carrier.

This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.

In one embodiment, the therapeutically effective amount is between about 0.03 and about 1000 mg per day.

In one embodiment, the therapeutically effective amount is between about 0.30 and about 300 mg per day.

In one embodiment, the therapeutically effective amount is between about 1.0 and about 100 mg per day.

In one embodiment, the disorder is depression.

In one embodiment, the disorder is anxiety.

In one embodiment, the disorder is obesity.

In one embodiment, the disorder is urge incontinence.

The invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.

The invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject’s depression.

The invention provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject’s anxiety.

The invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject's urge urinary incontinence.

The invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.

The invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.

The invention provides the method of treating overactive bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject’s overactive bladder. .

The invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be alleviated by treatment with an MCH1 antagonist, wherein the MCH1 antagonist is the compound of the invention.

The invention provides the method of alleviating the symptoms of a disor4der in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is the compound of the invention.

Detailed Description of the Invention

This invention provides a compound having the structure:

I’

R N Rg nad N77

WwW n p 1,

Vv R Rg '

X

I’

R N Rg my ov” N77

V. n pe —¥1

R RS m ¥ ]

Re v

R N R , or 6 ’ \ \ J

Tm

R Rg

Y -

I aad N77

N

« X n x —t] ; m

R Rg

Y wherein each V is independently phthalimide, -aryl, phenoxy or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F;

Cl; Br; I; CORs; COsRs; -OCORs; -CON(Rs),; -N(Rs)CORs; CN; -NO;z; -N (Rs) 2; -ORs; -SRs; (CH) (ORs; (CH2) qRs; (CH) ¢SRs; straight chained or branched C.-C, alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C.-C, alkenyl, C,-C; alkynyl; aryl; phenoxy; C3;-C; cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each W is independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more FF; Cl; Br; I; COR;; -OCORi;; COzRj3; -CON (R3)2; -N(R3)COR;; CN; -NOz; -N(R3)2; =-OR3; -SRi; (CH) ORs; (CH;)4SR3; straight chained or branched C;-C, alkyl, monofluorocalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C,-C; alkenyl, C;-C; alkynyl; aryl; phenoxy; C;-C; cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein X is hydrogen or - ORs, provided that when X is -OR; the V geminal to X cannot be phthalimide; wherein Y is hydrogen, =0 (carbonyl oxygen), OR;, OV,

COV, =NNHV, =NNRs, NZRs;, NZV, NCONV (ureas), NCONRs, NRj, carbazole, indole or phthalimide; wherein each R is independently -H; -F; straight chained or branched Ci1-Cy alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C:-C, alkenyl or alkynyl; -N(R3)2; -NOz; -CN; -COxR3; -OCOR;; -OR;3; or -N(R3)COR;; -CON(R3)2; : wherein each Rj; is independently -H; straight chained or branched C,-C; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C,-C; alkenyl or alkynyl;

C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each Rs is -H; -NO;; -N;; -CN; straight chained or branched C1-Cy alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C;-C; alkenyl or alkynyl; C3-Cy cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3),; =-ORj3; - (CHz)pORi; -CORj3; -CO2R;; -OCOR;; -CON(R3)2; -N(R3)COR;; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; CORg; COxRi; -OCOR3; -CON(Ri)2; -N(R3;)COR;; CN; -NO;; -N(Ris)2; -ORg; -SRs; (CHz)ORS6; (CH2) gSRs; straight chained or branched C;-C; alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C.-C, alkenyl, C.-C, alkynyl; C3-Cy cycloalkyl,

monof luorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein Rg is. -H; straight chained or branched C;-C, alkyl, monofluorocalkyl ox polyfluoroalkyl; straight chained or branched C.-C; alkenyl or alkynyl; GC;-C cycloalkyl, wmonofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)z; -ORi; -(CHz)pOR3; -CORj; -COzR3; -OCOR3; -CON(Ra)z; -N(Ra)COR,; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;

COR;; CO,R3; -OCOR3; -CON(R;3)2; -N(R3)COR3, CN; -NO;; -N(R3) 2; -0OR3; ~-SRj; (CH2) qOR3; (CH2) ¢SR3; straight chained or branched C1-Cy alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; aryl; benzyl; straight chained or branched C;-C; alkenyl, C:-C; alkynyl; C3-Cy cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein Z is CO, SO, or SO;NRg; } wherein each m is independently an integer from 0 to 3 inclusive; wherein each n is independently an integer from 0 to 5 inclusive; wherein each p is independently an integer from 1 to 7 inclusive; and . wherein q is an integer from 1 to 3 inclusive; or a pharmaceutically acceptable salt thereof. od

As used in the present invention, the term “cycloalkyl” includes GC3-Cy cycloalky moities which may be substituted with one or more of the following: F; CN; -NO,; straight chained or branched C;-C; alkyl, straight chained or branched C;-C; monofluoroalkyl, straight chained or branched C;-C; polyfluoroalkyl, straight chained or branched C,-C; alkenyl, straight chained or branched C2-Cy alkynyl; Ci-Cy cycloalkyl, Ca-Cy monofluorocycloalkyl, C;3-C; "‘polyfluorocycloalkyl, Cs-Cq cycloalkenyl, -N(Rs),; -OR3; -NCORsz; -COR3; -COzR;; -CON(R3)2 or (CH;)p-O- (CH3)q-CHs.

In the present invention, the term “cycloalkenyl” includes Cs-Cy cycloalkenyl moities which may be substituted with one or more of the following: -F; -Cl; -Br, -I; CN; -NO,; straight chained or branched .

C:-C, alkyl, straight chained - or branched C:-Cq monofluoroalkyl, straight chained or branched CC;-Cy polyfluoroalkyl, straight chained or branched C,;-Cy alkenyl, straight chained or branched C.-C; alkynyl; C;3-C; cycloalkyl, C3-Cq monofluorocycloalkyl, C3-Co polyfluorocycloalkyl, Cs-C; cycloalkenyl, -N(R3)2; -ORj3; -NCOR3; =-COR3; -COzR3; -CON(R3)2 or (CHz)p-O-(CHj)n-CH;.

As used in the present invention, the term “heteroaryl” is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, | pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazzolyl, thiadiazolyl,

pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

In addition, the term “heteroaryl” is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.

Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [blthiazolyl, imidazo[2,1-b]lthiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl. i5 B

The term ‘“hetercaryl” also includes those chemical moieties recited above which may be substituted with one or more of the following: -F; -Cl; -Br, -I; CN; -NO,; straight chained or branched C,-C; alkyl, straight chained or branched C;-C; monofluoroalkyl, straight chained or branched C;-C; polyfluorocalkyl, straight chained or branched C;-C; alkenyl, straight chained or branched C,-C; alkynyl; C3-C, cycloalkyl, C3-Cq monofluorocycloalkyl, C;-C; polyfluorocycloalkyl, Cs-C; cycloalkenyl, -N(Ra)2; -ORa; -NCOR3; ~COR;; _CO,Rs; -

CON (Rs); or (CH;)p-O- (CH3)n-CHa.

In still another embodiment of the above described invention, the compound has the structure:

H o

R “LR

Co J A i

W I 4

R

Y H

R R rx §°

VA n 4 !

R

Ho

I a ~LRe \ .

Ir — B

Vv R

H x 5 ~c Re

AR OHS 8 n \%

In a further embodiment of the instant invention, Re is ] straight chained or branched C;-C, alkyl; Ca-Cy cycloalkyl; -N(R3)a; -ORs; -(CH;)pOR;; aryl, benzyl or heteroaryl, optionally substituted with one or more F;

Cl; Br; I; -OR;; -(CHz)qOR3; or straight chained or branched C;-C; alkyl. - 15

I

In an embodiment of the present invention, the compound has the structure: . o

R 6 . od | R \ ; OY fh 7A ’ _— 0

R

: 0

H

R EN Rs / x C

V. n N 3 | ) — 0)

R

0]

In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR;; (CHz)qOR;; straight chained or branched C.-C, alkyl; C;-C; polyfluorocalkyl; or phenoxy.

In one embodiment of the present invention, the compound . is: . ls) 0

In one embodiment, the compound is: (OY 0 0

In one embodiment, the compound is:

Po (OY / (0) (0)

In another embodiment of the present invention, the compound has the structure: 0

H

R NY Par

S

4 x Io

N \ n

Vv 0

R

OR,

H

R N Fe ’ . / x C . N \ I °

V. n o \, —_—

OR,

In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR3; (CHz)qOR3; straight chained or branched C,-C; alkyl; C;-C; polyfluoroalkyl; or phenoxy.

In another embodiment of the present invention, the compound is : /

NH . =

In one embodiment, the compound is . NH . =

In a further embodiment of the present invention, the compound has the structure: : 0

H

R Ng Re

S

Y x or — Sy

Vv 0

R ov

H

R NG Fs

FX

N \ | -

Vv - . A—— 0

R - ov

In another embodiment of the present invention, at least one V is phenyl optionally substituted with one or more

F; Cl; Br; -ORi; -CORj;(CHz)qOR3; straight chained or branched C;-C; alkyl; C;-C; polyfluoroalkyl; aryl or phenoxy.

In yet another embodiment of the present invention, the compound is . d o—

NH

= : 5 In one embodiment, the compound is

O— £ OQ

NH ) =

In one embodiment, the compound is

NH

=

In one embodiment, the compound is

RF

OQ

NH

. =

In one embodiment, the compound is ] 0

NH a

In one embodiment, the compound is : R io} N 7 jo] na

In an embodiment of the present invention, the compound has the structure:

H 2 x JL / \ 8 i or

AX

.

H x IN 7 I

ADT

Y

10 . . In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or . 15 more F; Cl; Br; -OR;; (CHz)qORa; straight chained or branched C;~C; alkyl; C;-C; polyfluoroalkyl; or phenoxy.

In yet another embodiment of the present invention, the compound is - N

F

) F NH bd

F oO : F

FF

In one embodiment, the compound has the structure:

OQ

N~H oO

Q a -

F F

In one embodiment, the compound has the structure:

OQ

N—H . O -

Or 0 O

In one embodiment, the compound has the structure:

OY

N-H oO cl

In one embodiment, the compound has the structure:

OQ

N—H } oO dg cl ca :

In one embodiment, the compound has the structure: : ~ _N N—H }

N = by . C

In one embodiment, the compound has the structure:

N

— N—H

N 0 \ ps

In one embodiment, the compound has the structure: ‘ - . 7 \

N—H

: In one embodiment, the compound has the structure:

OC

~ F F

In an additional embodiment of the present invention, Y is hydrogen and V is phthalimide.

In an additional embodiment of the present invention, Rg is straight chained or branched C;-C; alkyl; C3-Cy cycloalkyl; -N(R3)z; -OR3; -(CHz)pOR3; aryl, benzyl or heteroaryl, optionally substituted with one or more F;

Cl; Br; I; -OR3; -(CH)qOR3; or straight chained or branched C;-C; alkyl. ] :

In a further embodiment of the present invention, the compound is

N 0 ‘

H

No ~~ ~N . 0

In one embodiment, the compound has the structure:

H

R — NR

OF Y

- v— Rr 0

N

N\

NH

AY

In one embodiment of the compound, at least one V is phenyl or heteroaryl optionally substituted with one or more F; Cl; Br; I; Rs; -ORs; -(CHz)qORs; -(CHz)gRs; straight chained or branched C;-C; alkyl; C;-Cy monoflouroalkyl or polyflouroalkyl; or phenoxy.

In one embodiment, the compound has the structure: =

ZN

In one embodiment, the compound has the structure:

R ) Re : 0 ad

OY

, R

H \) . :

In one embodiment of the compound, V is phenyl which is optionally substituted with one or more F; Cl; Br; -ORs; - (CH) qORs; -(CH3)qRs; straight chained or branched C,-C,; alkyl; C;-C, monoflouroalkyl or polyflouroalkyl; or phenoxy.

In one embodiment, the compound has the structure: ’ " .

N—H

In one embodiment, the compound has the structure: i : R N

N EY ye » N\ / © . X R

Y

In one embodiment, the compound has the structure:

R H

N

Cr n \ / ©

VZN R

In one embodiment, the compound has the structure:

N

Q ~

Cl SN, N—H o H 0

O-N; 5S

In one embodiment, the compound has the structure:

T i = _N = ye

N \_7

H n 0 . R

Oo

In one embodiment of the compound, Rs is straight chained or branched C,-C; alkyl; C;-C; cycloalkyl; -N(Rg)2; -ORg; -(CH;)qORs; -CH(Rg)2; -(CHz2)gRs ; or aryl, benzyl or heteroaryl, wherein the aryl, benzyl or heteroaryl is optionally .substituted with one or more F;

Cl; I; Re; -N(Rg)2; -ORe; - (CH;) ORs; = (CH;)qRe; Or straight chained or branched C;-C, alkyl.

In one embodiment, the compound has the structure: oI

Wa On URE i 2s

In one embodiment, the compound has the structure:

N

Cl \ J ad 0

N

NH H pa ct O - 5 -

In one embodiment of the compound, X is hydrogen and Y is carbazole optionally substituted with one or more F;

Cl; Br; Rs; -ORs; -(CHz)qORs; -(CHz)qRs ; straight chained " or branched C;, - C; alkyl; or C;-C; monoflouroalkyl or i0 polyflouroalkyl; or phenoxy.

In one embodiment, the compound has the structure:

N N ea ita )

In one embodiment, the compound has the structure:

N o , »

H

)

In one embodiment of the compound, Y is hydrogen and

V is an indole, which can be optionally substituted with one or more Fj; Cl ; Br; Rs; ~-COzRs; -ORg FH (CH,) gORs; - (CH,) Rs; straight chained or branched C; - C,; alkyl; C;-C, monoflouroalkyl or polyflouroalkyl; or phenoxy on the 1, 2, 3, 4 , 5 6 or 7 positions.

In one embodiment, the compound has the structure:

R

SOQ n

Ch v2

N =

In one embodiment, the compound has the structure: ad N—H . N O i - J .

In one embodiment, the compound has the structure:

O42 ee al N-H

N oO . (ug 15 .

In one embodiment, the compound has the structure:

OY veal NH

NCH ps

In one embodiment, the compound has the structure: 4 =

In one embodiment, the compound has the structure:

N =

In one embodiment, the compound has the structure: / N lo} oo

N—H \ =

N

. . i . H . : In one embodiment, the compound has the structure:

OQ

CI o ns

H .

In one embodiment, the compound has the structure:

Of o

S Oo

In one embodiment, the compound has the structure: (038 0 NOY -H

N

"0

In one embodiment, the compound has the structure:

R

ARO n —~H

S R N

. ZN

In one embodiment, the compound has the structure:

NO rel N-H l = on

In one embodiment, the compound has the structure:

NO

Po lain.

Oo 0 =<

F

In one embodiment, the compound has the structure:

NOD

. N-H

Oo : N

O- } In one embodiment, the compound has the structure:

NO

N N-H = 0

The present invention provides a compond having the srucuture:

X X

. JS R, PS Ry

X Nn" N Nn )

R R . 2 2 i

TARE TOA

Rs R, Rs R,

X :

R or 1

A nN —

Ry R,

AT,

Rs Ry wherein each X is independently O or S; wherein g is 1 or 2; : wherein each R; is independently H; -(CH,)XR3; - (CH,) C(X)N(R3) 2; -(CH,):COsR3; -COzR3;; straight chained or branched C;-C, alkyl optionally substituted with -N(R3)2; -CON(R3)2 or -N(R3)C(O)Ri; straight chained or branched C;-C; alkenyl, or alkynyl; or C;-C; cycloalkyl or

Cs-C; cycloalkenyl; wherein each t is independently an integer from 1 to 4 inclusive; : wherein each R; is independently H; straight chained or branched C;-C, alkyl, straight chained ox branched C,-C, . alkenyl, or alkynyl; or C;-C; cycloalkyl or Cs-Cy cycloalkenyl;

wherein R, is aryl, heteroaryl, C;-C, alkyl substituted with one or two aryl, or C;-C; alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be . 5 substituted with one or more of F, Cl, Br, I, -CN, -NO,, -N(Ri)z, -CORji, -(CH,)nXR3, -(CH:)aC(X)NRj, - (CH,) nN (R3) C(X) R3, - (CH;) nCO2R3, - (CH;) nOCOR;, straight chained or branched C;-C; alkyl, monofluoroalkyl OR polyfluorocalkyl or straight chained or branched C,-C; aminoalkyl, alkenyl or alkynyl, or C;3;-C; cycloalkyl or

Cs-C; cycloalkenyl; wherein each n independently is an integer from 0 to 7 inclusive; wherein Rs; is H; aryl, C;-C; alkyl substituted with aryl, heteroaryl, or C;-C; alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -NO,, -N(R3)z, -COR;, - ] (CH;) nXRa, -(CH2),C(X)NR3, -(CH;),CO;R;, straight chained or ~ branched C;-C; alkyl, monofluoroalkyl, polyfluoroalkyl or . . carboxamidoalkyl, or straight chained or branched C,-C, aminoalkyl, alkenyl or alkynyl, or C;3;-C; cycloalkyl or ~ Cs-C; cycloalkenyl; where Rs and one R; on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C;-

C,; cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S; i - ’ wherein R; is

Rg

Y Rg , o. m ul Ng , or

Z—N . ed N . nR7

Rg

Rg v Y R 8 .

FA Ng” i . Z—N ’ m R7

Rg ’

So Rg . : wherein each V is independently aryl, phenoxy or . heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F; Cl; Br; I;

COR5; CO2Rs; -OCORs; -CON(Rs)2; -N (Rs) CORs; CN; -NO3; -

N(Rs)2; -ORs; -SRs; (CHz)qORs; (CH3z)qSRs; straight chained or branched C;-C; alkyl optionally substituted with -

CON (Rs), -N(Rs)C(O)R; or N(R3)z, straight chained or branched monofluoroalkyl or polyfluoroalkyl, straight chained or branched C;-C; alkenyl, C,-C; alkynyl; ) phenoxy; or (C3-C; cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each Rg is independently H; (CH) XR3; (CHz) :C (X) NR; (CH,) (N (R3) C(X) Ra; (CH) tCOzR3; (CH) tOCOR3; straight chained or branched C;-C;, alkyl optionally substituted with -CON(R3); or -NC(O)R3; straight chained or branched C,-C; alkyl substituted with -N (Rj); straight chained or branched C,-C; alkenyl or alkynyl; or C3-C, cycloalkyl or Cs-C; cycloalkenyl; where each R; is independently H; F; Cl; Br; I; -CORa; -

CO;R3; - (CH2)nXRa; -(CH2)uN(R3)C(O)R3; .(CHz)aC(X)N(R3)2; - (CH) nCO,R;; ~-CN; -NOz; -N(R3)2; straight chained or branched C.-C alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C;-C, alkenyl or alkynyl; C3-Cy cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cs-Cy cycloalkenyl, wherein the alkyl, aminoalkyl, ~ carboxamidoalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl , cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, CI,

Br, I, -(CHz)nXR3, -CORj, -(CH;)aC(X)N(R3)2,- (CHz)nCOzRy, -

CN, =-NO,, -(CH3).N(R3)C(O)R3; -N(R3)2, =-SO2R;, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C;-C, alkenyl or alkynyl, or C3-Cy cycloalkyl, ] monofluorocycloalkyl, polyfluorocycloalkyl or Cs-C, cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, C1,

Br, I, -(CH)uXRy, -CORa, - (CHy)aC(X)N(R3)g

- (CH;) ,CO2R3, - (CH) nN (R3)C(O)R3; -CN, -NOg, -N(R3),, -SOzR3, straight chained or branched C;-C; alkyl, ’ straight chained or branched C;-C; monofluoroalkyl or polyfluoroalkyl, straight chained or branched C.-C, alkenyl or alkynyl, or Ci-Cy cycloalkyl, monof luorocycloalkyl, polyfluorocycloalkyl or Cs5-Cq cycloalkenyl; wherein B is CO, SO, or SO,;NRg; wherein Rg is -H; straight chained or branched C;-C; alkyl, wonofluorocalkyl or polyfluoroalkyl; straight chained or branched C,-C; alkenyl or alkynyl; GC3-Cy cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)a; -NR3C(O)Ri; =-OR3; -(CH2)pOR3; -

CORj3; -COzR3; ~-OCOR3; ~CON (R3) 2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I;

COR3; COzR3; -OCOR3; -NR3C(O)Rj3; -CON (R3) 3; CN; -NOp; -

N(R3)2; -OR3; =-SR3; (CH)qOR3; (CH2) ¢SR3; straight chained or branched C;-C; alkyl optionally substituted with -

CON (R3)2, -NR3C(O)R; or -N(R3); straight chained or branched ~~ monofluoroalkyl, polyfluoroalkyl; straight chained or branched C,-C; alkenyl, C;-C; alkynyl; C3-C; cycloalkyl, wmonof Juorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl; wherein each m independently is an integer from 0 to 3 inclusive; wherein Z is

-Y- ’ 0 R, Rg

PY i t t

Y n 4

Ry . R, Rg

R t s t n ’

R, Re . Q R, Re

Rg t t ’ n

R, Rg : Rg 0 Rg

R, Rg t n ,

Y t t

Re R,

Ry Rg 0 Raz

P'S i j n m P< 9

Y Fo) ’ ’ } Rg a. oo

0 Way Ro

N ) Ro A o m 6 }

Re Ry N6 0 Ro Re

Ro Ro mn Y A , Or

Ro Re

Ra Ro 0 R, Rs > m n . ] Ra Re

Ra Ro or C,-C; alkenyl, wherein the C;-C; alkenyl may be unsubstituted or substituted with one or more Ry groups; wherein each Ry; is independently H; F; Cl; Br; I; -- (CHz) mXR3; (CH3) nC (X)NR;; (CHz) mCOzR3; straight chained or branched C;-C; alkyl, monofluoroalkyl, polyfluoroalkyl, ’ aminoalkyl, or carboxamidoalkyl; straight chained or branched C;-C; alkenyl, or alkynyl; or C;-C, cycloalkyl or ) Cs-C; cycloalkenyl;

wherein R,, is H; (CH;)¢XR3; (CH). C(X)NR3; (CH,) :COzR3; straight chained or branched C.-C alkyl, carboxamidoalkyl; straight chained or branched C;-C; aminoalkyl, alkenyl, or alkynyl; or C;-C cycloalkyl or

Cs-C,; cycloalkenyl; wherein Y is S, O, or NRyp; wherein each p is independently an integer from 1 to 7 inclusive; : or a pharmaceutically acceptable salt thereof. . :

In a further embodiment of the present invention, the compound has the following structure:

X X .

JY Ry : JS R

X Nn” N gl : } — > ~~.

R, R, or R,™\ R, .

Ad. LAH, :

Rg R, Rg Ry : In an additional embodiment of the present invention, the compound has the structure:

0 Re Rs

Ry

AY

- N—2Z—N re pi ; or

R

; 2 Ry Reg 0 0 Rg

Ae “Nz 3 0

N—Z: we ~( JN .

R

PR Rr &

In an additional embodiment of the present invention, the compound has the structure:

A / \

N—Z—N

Rg JS N.__Rs -

Ro Ry T

In one embodiment of the present invention, Z is: - 0 R, Rg

R .

PR J N

Y n -

R, Rg

Ry

In one embodiment of the present invention, Z is:

F

} : F : 0 —{ H. NH

In an additional embodiment of the present .invention, the compound has the structure:

Ra Re ’ rs

R te |° t . i n L]

R; Rg

Rg

In one embodiment of the present invention, the compound has the strucuture:

FE

F

ANN

4 GP

N

“No ™ 0)

This invention provides a compound having the structure: + . va

Rj N—H o=

Ro wherein R;, is hydrogen, straight chained or branched

C;-C; alkyl, monofluorocalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, =I, -CN, -NO,, -CH;, -CF;, -COCH;, -COzR;, phenyl, phenoxy or straight chained or branched C;-C; alkyl; wherein R, is straight-chained or branched C;-C, alkyl or cyclopropyl; : wherein R; is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, ci, -Br, -I, -CN, -NO;, straight chained or branched C;-C; alkyl; wherein A is -H, -F, -Cl1, -Br, -CN, -NO,, -COR3, -COzRj3, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O or NH; ’ . 25 wherein n is an integer from 0 to 5 inclusive;

In one embodiment, R; is aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO;, -COCH;,

-CO,R,, straight chained or branched C;-C; alkyl: . wherein R; is phenyl; , 5 wherein A is H; and wherein X is O.

In one embodiment, R, is isopropyl.

In a preferred embodiment, X is NH, R; is alkyl and n is 1 or 2.

In the most preferred embodiment, X is O, R; is 3-acetyl phenyl, R, is isopropyl, Rs; is phenyl and n is 1.

In one embodiment, the compound has the structure: 0]

N

= :

In one embodiment, compound has the structure: d o—

N Co : =

In one embodiment, Ri; is hydrogen, straight chained or branched C;-C; alkyl; and wherein Rj; is aryl.

In one embodiment, R,.is isopropyl; and A is hydrogen. . 5 . In one embodiment, .the compound has the structure:

N . =

In one embodiment, the compound has the structure: : N . : ps

The present invention also provides a compound having the structure:

A

=|=

Ry N \ /

In 0) N—H o=

Ra wherein R; is aryl or heteroaryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, -OCHa, phenoxy, fused cyclopentanyl, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl;

wherein R, is straight-chained or branched C;-C, alkyl or cyclopropyl; . 5 wherein A is -H, -F, =-Cl, -Br, -CN, -NO,, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 1 to 5 inclusive.

In one embodiment, R, is isopropyl; and wherein n is 2. N

In a preferred embodiment, n is 2 and R; is isopropyl.

In one embodiment, the compound has the structure: ~ — Pe ’ 0 lo} 25 . in one embodiment, the compound has the structure: oR , [¢} (o]

In one embodiment, the compound has the structure: o

Lr {

F N n- . i”

In one embodiment, R; is thienyl; and wherein A is H.-

In one embodiment, R; is isopropyl.

In one embodiment, the compound has the structure:

O oo Oo {

S N nN 10 .

The invention provides a compound having the structure:

A

=|= /—N

W \_/

N-H 7 o=(

R2 wherein W is : . )

A

0) bE ® | Caan or Zz ;

N Ry i

Ry H ) i wherein each R, is independently hydrogen, methyl or ethyl; wherein R, is straight-chained or branched C;-C, alkyl or wherein R, is straight- chained or branched C;3-C4 alkyl or cyclopropyl; wherein R; is hydrogen, aryl or heteroaryl, wherein the . 5 aryl or heteroaryl is optionally substituted with one or more -H, -F, -Cl, -Br, -I, -CN, -NO,, straight chained or branched C,-C; alkyl. wherein each A is independently -H, -F, -Cl, -Br, -CN, -NO,, -COR,, -CO;R;, straight chained or branched C;-C alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O, NR;, CO or may be absent; and wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO;, straight chained or branched C;-C; alkyl.

In one embodiment, W is ’ . H A a ¥Z . 4 and wherein X is O or may be absent.

In one embodiment, R; is isopropyl. : .-

In one embodiment, the compound has the structure:

OQ a (0) “

Oo .

F F

In one embodiment, the compound has the structure: ’ fo) . . _. } o) (LL N

In one embodiment, W is

Cx Ry

Ry

In one embodiment, A is -H, -F, -Cl, -Br.

In one embodiment, R, is isopropyl; and A is hydrogen.

In one embodiment, the compound has the structure: iS

RS pe

This invention provides a compound having the structure:

A

“OQ : \_/

N-H o=

R2 wherein W is = N ZF N

Ry Ry wherein R; is hydrogen, straight chained or branched

C;-C, alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl1, -Br, -CN, -NO,, =-OCH3, -COCH;, -CFi, phenyl, -gtraight chained or branched C;-C; alkyl; wherein Rj is straight-chained or branched C3-C, alkyl or cyclopropyl; 1s "wherein A is -H, -F, -Cl, -Br, -CN, -NO;, -COR;, -CO.Ri, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl. : wherein each B is independently -H, -F, -Cl, -Br, -I, -CN, -NO,, -COR;, -COzR;, -OCH;, -OCF3;, -CF,, straight chained or branched ¢;-C; alkyl, wmonofluorocalkyl or . polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more -F, -Cl, -Br, -CN, -NO,, -COR;, -CO;Ri,

-0OCH,, -OCF3, ~-CF, or straight chained or branched C1 -C3 alkyl.

In one embodiment, W is ‘ os {8

Z J

Ri

In one embodiment, R; is hydrogen or phenyl optionally : substituted with one or more -F, -Cl, -Br, -CN, -NO,, straight chained or branched C;-C; alkyl. Co :

In one embodiment, R; is isopropyl. :

In one embodiment, the compound has the structure:

N

_ N

A N-

Cl N ]

In one embodiment, the compound has the structure:

N

BD N od 0

N

This invention provides a compound having the structure:

A

“I= = [/==N \ / ‘ Re~~ / \ ;

N\ R N-H 4 y 0

Ry Ra 5- wherein R; is hydrogen, straight chained or branched

C.-C; alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -CN, -NO,, -CF;, -OCH;, straight chained or branched Ci-C; alkyl; wherein R; is straight-chained or branched C;-Cs alkyl or cyclopropyl; wherein R; is -H, -F, -Cl, -Br, -I, -CN, -NO,, -CF,, -OCHs, or straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl, or a phenyl ring fused to C¢ and C; of the indole moiety; wherein Rs; is hydrogen or aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, -CFs, straight chained or branched C;-C; alkyl; wherein A is -H, -F, -Cl, -Br, -CN, -NO,, straight chained or branched (;-C; alkyl, monofluoroalkyl or . 25 polyfluoroalkyl; and ’ wherein n is an integer from 2 to 4 inclusive.

in one embodiment, Rs is - wu, -F, -Cl, -Br, -I, -CN, -

NO,, -OCF; or -OCH3; and wherein R, is hydrogen or phenyl optionally substituted } 5 with one or more -F, -Cl or -CF;.

In one embodiment, R, is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -NOj, : -CF;, -OCH; or straight chained or branched C;-C; alkyl;

In one embodiment, R, is isopropyl.

In one embodiment, the compound has the structure: ’

N

% N

O A

. N

CL N

15 .

In one embodiment, the compound has the structure: r py

FO

O .

Cl

In one embodiment, the compound has the structure:

N

~ N . . | . as

This invention provides a compound having the structure:

A

. N =|= - Ra : Rif ~~ \_¢ E 0 Ra wherein each R; is independently hydrogen or CHj; wherein R, is straight-chained or branched C;-Cs alkyl or cyclopropyl; : wherein R, is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or.omne or more -F or -Cl; . wherein A is -H, -F, -Cl, -Br, -CN, -NO,, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; } wherein X is (CHy),, COCH, or CONH; .. .In one embodiment, R; is phenyl optionally substituted with one or more -¥; and wherein A is hydrogen.

In one embodiment, X is CONH. * In one embodiment, R, is methyl. : In one embodiment, the compound has the structure:

Fs > F a NNN NY 0— N . 0}

In one embodiment, the compound has the structure:

F vi ~N

OQ

N—-X N—H ; Xo wherein each Y is independently hydrogen or -F.

In one embodiment, the compound has the structure:

F .

F< ® JF

R

: | 6) (ON NNN YY o— N 0

In one embodiment, the compound has the structure:

F .

AF

[a 0 - : 0 N

In one embodiment, Rs; is benzyl optionally substituted with a methylenedioxy group or one or more -F or -Cl.

In one embodiment, the compound has the structure:

F x A

Y

R N ) Q ) :

Ry 1 ~~

N—X N—H o i wherein each Y is independently hydrogen or -F.

In one embodiment, the compound has the structure:

F. (0)

N

0 N (0)

In one embodiment, the compound is enantiomerically pure.

In one embodiment, the compound is diastereomerically pure.

In one embodiment, the compound is enantiomerically and diastereomerically pure. * . 20 . . oo

This invention also provides a pharmaceutical . composition comprising a therapeutically amount of a compound of the invention and a pharmaceutically acceptable carrier.

In one embodiment, the amount of the compound is from about 0.0lmg to about 500mg. in one embodiment, the amount of the compound is from about 0.1lmg to about 60mg. ’ 10 In one embodiment, the amount of the compound is from about 1mg to about 20mg.

In one embodiment, the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution. ]

In one embodiment, the pharmaceutical composition : : consists of a carrier which is a solid and the composition is a tablet. ]

In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition : ie a suppository. N ° The invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable ‘carrier. :

This invention also provides the method of treating a . subject suffering from a disorder selected. from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.

In one embodiment, the disorder is depression. Co

R-S Ce : In one embodiment, the disorder is anxiety.

In one embodiment, the disorder is obesity.

In one embodiment, the disorder is urge incontinence.

The invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. .

The invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject's : depression.

Lo. : Co ". The ‘invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject’s urge urinary incontinence.

The invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of a. "the invention effective to induce weight loss in the subject.

The invention provides the method of managing obesity in } a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject. . 25 The invention provides the method of treating overactive " bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject’s overactive bladder. . 30

The invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be alleviated by treatment with an MCH1 antagonist, wherein the MCH1 antagonist is the compound of the invention. ] 5 The invention provides the method of alleviating the symptoms of a disor4der in a subject, which comprises administering to the subject an amount .of an MCH1 antagonist effective to alleviate the symptoms, ' wherein the MCH1 antagonist is the compound of the invention

As used in the present invention, the term “heteroaryl” is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

In addition, the term “heteroaryl” is used to include fused bicyclic ring systems that may contain one or more ’ heteroatoms such as oxygen, sulfur and nitrogen.

Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, . benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, . benzo[blthiazolyl, imidazo[2,1-b]lthiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, 30 .pteridinyl, quinolinyl, isoguinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.

The term “heteroaryl” also includes those chemical moieties recited above which may be substituted with one ) or more of the following: -F, -Cl, -Br, -I, CN, -NO, straight chained or branched C;-C; alkyl, straight ~ 5 chained or branched C;-C; wmonofluoroalkyl, straight chained or branched C;-C; polyfluoroalkyl, straight chained or branched C,-C; alkenyl, straight chained or branched Cy-Cy alkynyl; C3-Cy cycloalkyl, C3-Cq : monofluorocycloalkyl, C;-C; polyfluorocycloalkyl, Cs-Cq cycloalkenyl, : ol The term “heteroaryl” further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.

Co In the present invention, the term “aryl” is phenyl or ” naphthyl.

The invention provides for each pure stereoisomer of any of the compounds described herein. Such stereoisomers ° may include enantiomers, diastereomers, or E or Z alkene or imine isomers. The invention also provides for stereoisomeric mixtures, including racemic uixtures, diastereomeric mixtures, or E/Z isomeric mixtures. : oC 25° ~~ Stereoisomers can be synthesized in pure form (Négradi, -

Co M.; Stereoselective Synthesis, (1987) VCH Editor Ebel,

H. and Asymmetric Synthesis, Volumes 3B 5, (1983)

BE Academic Press, Editor Morrison, J.) or they’ can be ° , resolved by a variety of methods such as crystallization and chromatographic techniques (Jaques, J.; Collet, A.; \ Wilen, S.; Enantiomer, Racemates, and Resolutions, 1981,

John Wiley and Sons and Asymmetric Synthesis, Vol. : 2, 1983, Academic Press, Editor Morrison, J).

In addition the compounds of the present invention may ] : 5 be present as enantiomers, diasteriomers, isomers or two or more of the compounds may be present to form a racemic or diastereomeric mixture.

The compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure. Included in this invention are pharmaceutically acceptable salts and complexes of all : of the compounds described herein. The acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein. The acids include, but are not limited to, the following inorganic - acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The acids include, but are not limited to, the following organic acids: i acetic acid, malonic acid, succinic acid; fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic : acid, benzoic acid, glycolic acid, lactic acid and : mandelic acid. The bases include, but are not limited a to ammonia, methylamine, ethylamine, propylamine, dimethylamine, * diethylamine, trimethylamine, } triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention : : further provides for the hydrates and polymorphs of all of the compounds described herein. . 30

The present invention includes within its scope prodrugs . : of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds

Claims

What is claimed is: . 1. A compound having the structure: + She Rj N—H o=( Re wherein R; is hydrogen, straight chained or branched C;- C; alkyl, monofluorocalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or wore -F, -Cl, -Br, -I, -CN, - NO,, -CH,, -CF3, -COCHi;, -COzR2, phenyl, phenoxy or straight chained or branched C;-C; alkyl; wherein R, is straight-chained or branched C3-C4 alkyl or cyclopropyl; } wherein R; is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more - F, -Cl, -Br, -I, -CN, -NO,, straight chained or branched

C.-C; alkyl; wherein A is -H, -F, -Cl, -Br, -CN, =-NO,, =-COR,;, -COzRj, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; ’ 25 wherein X is O or NH; and wherein n is an integer from 0 to 5 inclusive.

2. The compound of claim 1, wherein R; is aryl optionally substituted with one or more -F, -Cl, -Br, - I, -CN, -NO,, -COCHs, -CO;R;, straight chained or branched C,-C; alkyl; wherein R; is phenyl; wherein A is H; and wherein X is O.

3. The compound of claim 2, wherein R; is isopropyl.

4. The compound of claim 3, wherein the compound has the structure: N ip.

5S. The compound of claim 3, wherein the compound has the structure: dq 0— fF OQ . \ .

i.

6. The compound of claim 1, wherein R; is hydrogen, straight chained or branched C;-C; alkyl; and wherein R;

is aryl.

7. The compound of claim 6, wherein R; is isopropyl; and A is hydrogen.

8. The compound of claim 7, wherein the compound has the structure: Oa

N .

=

S. The compound of claim 7, wherein the compound has the structure:

N . =

10. A compound having the structure: } R; N \ / In ; Oo N-—H oo R2 wherein R; is aryl or heteroaryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, -OCH;, phenoxy, fused cyclopentanyl, straight chained or branched C-Co alkyl, monofluoroalkyl or polyfluoroalkyl; wherein R, is straight-chained or branched C;-C; alkyl or cyclopropyl; wherein A is -H, -F, -Cl1, -Br, -CN, -NO,, straight chained or branched C;-C; alkyl, wmonofluoroalkyl or polyfluoroalkyl; and ) wherein n is an integer from 1 to 5 inclusive.

11. The compound of claim 10, wherein R, is aryl optionally substituted with one or more -F, -Cl, -Br, -I or straight chained or branched C,-C, alkyl; and wherein A is H. i

12. The compound of claim 11, wherein R, is isopropyl: and wherein n is 2.

13. The compound of claim 12, wherein the compound has the structure: — N : ) 0

14. The compound of claim 12, wherein the compound has the structure:

0 0

15. The compound of claim 12, wherein the compound has the structure: 0 LO g F N nA

16. The compound of claim 10, wherein R, is thienyl; and wherein A is H.

17. The compound of claim 16, wherein R, is isopropyl.

18. The compound of claim 17, wherein the compound has the structure: 0 OA { s N vl -

15 . ‘

19. A compound having the structure: A =|= —N W \_¢ N—H o=( R2 wherein W is

’ A H A (0 A or Z ; NR R, H wherein each R; is independently hydrogen, methyl or ethyl; wherein R, is straight-chained or branched C;-C; alkyl or cyclopropyl; wherein R; is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -H, -F, -Cl, -Br, -I, -CN, -NO,, straight chained or branched C;-C; alkyl. } wherein each A is independently -H, -F, -Cl, -Br, -CN, - NO,, -COR;, -CO;R;, straight chained or branched C;-Cy alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is O, NR;, CO or may be absent; and wherein Y is hydrogen, ‘aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, straight chained or ’ branched C;~-C; alkyl.

20. The compound of claim 19, wherein W is

H A AS ZZ f and wherein X is O or may be absent.

31. The compound of claim 20, wherein R, is isopropyl.

22. The compound of claim 21, wherein the compound has the structure: NO Oo “ a F F

23. The compound of claim 21, wherein the compound has the structure:

[0] [

24. The compound of claim 19, wherein W is CC N Ry

25. The compound of claim 24, wherein A is -H, -F, - Cl, -Br.

26. The compound of claim 25, wherein R; is isopropyl; } 5 and A is hydrogen.

27. The compound of claim 26, wherein the compound has the structure: CLT Uy N O J pe

28. A compound having the structure: A Ww == N \_/ N-—H o= R2 wherein W is B B > or <2 4 N ZN R, Ry wherein R; is hydrogen, straight chained or branched C;- C; alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more - F, -Cl, -Br, -CN, -NO,, -0CH,, -CO,CH;, -CFa, phenyl, straight chained or branched C;~C; alkyl;

wherein R; is straight- chained or branched C;-C4 alkyl or cyclopropyl; wherein A is -H, -F, -Cl, -Br, -CN, -NO;, -COR;, -CO2R;, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl. wherein each B is independently -H, -F, -Cl, -Br, -I, - CN, -NO,, -COR;, -CO;R;, -OCH;, -OCF;, -CF;, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more -F, -Cl, -Br, =CN, -NO;, -COR;, -COzR, -OCH;, -OCF,;, -CF; or straight chained or branched C;-Cq alkyl. . 29. The compound of claim 28, wherein W is ZN Ry

30. The compound of claim 29, wherein R; is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -NO,, straight chained or branched C;-C; alkyl.

31. The compound of claim 30, wherein R, is isopropyl.

32. The compound of claim 31, wherein the compound has the structure: i

OK N cb = ci N

33. The compound of claim 31, wherein the compound has the structure: N ) 9 N Oo

34. A compound having the structure: A =|= = [/1N \ / R3~=L ) A N\ R N—H

4 . N 0 wherein R, is hydrogen, straight chained or branched C;- C; alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more - F, -Cl, -Br, -CN, -NO,, -CF3, -OCH,;, straight chained or branched C;-Cs; alkyl; : : wherein R; is straight-chained or branched. C3-C, alkyl or cyclopropyl; wherein R; is -H, -F, -Cl, -Br, -I, -CN, -NO,, -CFi, -

OCH;, or straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl, or a phenyl ring ’ fused to Cs and C; of the indole moiety; wherein R, is hydrogen or aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -NO,, -CFj, straight chained or branched C;-C; alkyl; wherein A is -H, -F, -Cl1, -Br, -CN, -NO,, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; and wherein n is an integer from 2 to 4 inclusive.

35. The compound of claim 34, wherein R; is -H, -F, -Cl, -Br, -I, -CN, -NO,, -0OCF, or -0OCH;; and wherein R; is hydrogen or phenyl optionally substituted i with one or more -F, -Cl or -CF;.

36. The compound of claim 35, wherein R; is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -NO,, -CF;, -OCH; or straight chained or branched C,-C; alkyl;

37. The compound of claim 36, wherein R, is isopropyl.

38. The compound of claim 37, wherein the compound has

: . the structure:

N : = N ed ~r N } N

39. The compound of claim 37, wherein the compound has the structure: FF Fo N N NAS 0 ° Cl

40. The compound of claim 37, wherein the compound has - : the structure: Saal N ® : oO

41. A compound having the structure: : A ; =F Rs Rif ~~ \_¢ : N—X N-H 0] Ro wherein each R; is independently hydrogen or CHj; wherein R, is. straight-chained or branched C;-C4 alkyl or ’ 5 cyclopropyl; wherein R; is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more -F or -Cl; wherein A is -H, -F, -Cl, -Br, -CN, -NO;, straight chained or branched C;-C; alkyl, monofluoroalkyl or polyfluoroalkyl; wherein X is (CH;),, COCH, or CONH;

42. The compound of claim 41, wherein R; is phenyl optionally substituted with one or more -F; and wherein A is hydrogen.

43. The compound of claim 42, wherein X is CONH.

44. The compound of claim 43, wherein R; is methyl.

45. The compound of claim 44, wherein the compound has the structure:

Fx 8 F f 2 (0) (ON NTN ad . o—{ N Oo

46. The compound of claim 44, wherein the compound has the structure: F ve ~N R OQ N—X N—-H Ox o=(

0) . wherein each Y is independently hydrogen or -F.

47. The compound of claim 46, wherein the compound has the structure: ’ F Fx : F H A (CN SNS 7 o— N

O . j

48. The compound of claim 46, wherein the compound has the structure: F F 0 nA AN O.

N . 0—4 : N (0)

49. The compound of claim 41, wherein R; is benzyl optionally substituted with a methylenedioxy group or one or more -F or -Cl.

50. The compound of claim 49, wherein the compound has the structure: R - ye J R N R; 1 ~~ N—X N—H 0X o=< 0) ; ; wherein each Y is independently hydrogen or -F.

51. The compound of claim 50, wherein the compound has the structure: ; § A

F. 0 N o— N 0

52. A compound of claims 1 to 51, wherein the compound is enantiomerically pure.

53. A compound of claims 1 to 51, wherein the compound : is diastereomerically pure.

54. The compound of claims 52 and 53, wherein the compound is enantiomerically and diastereomerically pure.

55. A pharmaceutical composition comprising a therapeutically amount of a compound of any of claims 1 to 51 and a pharmaceutically acceptable carrier.

56. The pharmaceutical composition of claim 55, wherein the amount of the compound is from about 0.0lmg to about 500mg.

57. The pharmaceutical composition of claim 56, wherein the amount of the compound is from about 0.1lmg to about 60mg. ’ 25

58. The pharmaceutical composition of claim 57, wherein the amount of the compound is from about 1mg to about 20mg.

59. The pharmaceutical composition of claim 55, wherein the carrier is a liquid and the composition is a solution.

60. The pharmaceutical composition of claim 55, wherein the carrier is a solid and the composition is a tablet.

61. The pharmaceutical composition of claim 55, wherein the carrier is a gel and the composition is a suppository.

62. A process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of claims 1 to 51 and a pharmaceutically acceptable carrier.

63. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity.

64. The use of claim 63, wherein the therapeutically effective amount is between about

0.03 and about 1000 mg per day.

65. The use of claim 64, wherein the therapeutically effective amount is between about

0.30 and about 300 mg per day.

66. The use of claim 65, wherein the therapeutically effective amount is between about

1.0 and about 100 mg per day.

67. The use of claim 63, wherein the disorder is depression. Amended sheet 24/11/2004

68. The use of claim 63, wherein the disorder is anxiety. .

69. The use of claim 63, wherein the disorder is obesity.

70. The use of claim 63, wherein the disorder is urge incontinence.

71. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for reducing the body mass of a subject.

72. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for treating a subject suffering from depression.

73. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for treating a subject suffering from anxiety.

74. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for treating a subject suffering from urge urinary incontinence.

75. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for managing obesity in a subject in need of weight loss to induce weight loss in the subject.

76. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for inducing or maintaining weight loss in a subject.

77. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for treating a subject suffering from overactive bladder. oo Amended sheet 24/11/2004

78. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for treating a disorder wherein the symptoms of the subject can be alleviated with an MCH1 antagonist.

79. Use of a compound according to claims 1 to 51 for preparation of a medicament useful for alleviating the symptoms of a disorder wherein the symptoms of the subject can be treated with an MCHI1 antagonist. Amended sheet 24/11/2004